Immunosuppressive microenvironments are a major hindrance to current immunotherapy applications in solid tumor cancers. Patients with human papillomavirus (HPV)-induced oropharyngeal cancer (OPC) are an excellent example of this as marked elevations in systemic immunosuppression result in less than 50% response rates to immune checkpoint inhibitor (ICI) therapies, a new potent cancer immunotherapy. The long-term objective of this application is to aid in the development of effective combination immunotherapy platforms for the treatment of HPV-associated oral cancers. The overall goal of this research project, which is the next step in pursuit of that objective, is to determine if solid tumor conditioning to remove intra-tumoral immunosuppressive cells can enhance the efficacy of ICI therapies against HPV-induced OPC. To accomplish this goal three aims have been developed. Aim 1 will optimize and characterize an immunomodulatory nanoparticle platform which we hypothesize will promote significant activation of both innate and adaptive immune cell populations while minimizing the suppressive effects of various immunosuppressive cell populations. Aim 2 will assess the therapeutic efficacy and immunologic mechanism of our nanoparticles in combination with ICI therapies. We hypothesize that combination nanoparticle treatment will significantly enhance the efficacy of ICIs in a murine primary tumor challenge of HPV-related OPC by limiting immunosuppressive cells in the intra-tumoral space. Aim 3 will then characterize the induced systemic and immunologic memory effects of our combination therapy, which we hypothesize will both be greatly enhanced due to improved activation of tumor-specific T-cells. Various immunologic, biologic, and bioengineering techniques will be used to test our overall working hypothesis. These techniques include production and characterization of liposomal platforms, extensive use of preclinical murine models of HPV-related OPC, and immune microenvironment and mechanism studies. Overall, this project will help explain the role that immunosuppressive cell populations play in oral cancer immunologic avoidance. This could greatly improve oral health but generating new approaches to enhance patient responses to immunotherapies, thereby limiting the application of highly toxic treatment regimens used currently.